title: Dose-dependent neuroprotection of VEGF₁₆₅ in Huntington's disease striatum.
abstract: Huntington's disease (HD) is a devastating neurodegenerative disorder caused by abnormal polyglutamine expansion in the huntingtin protein (Exp-Htt). Currently, there are no effective treatments for HD. We used bidirectional lentiviral transfer vectors to generate in vitro and in vivo models of HD and to test the therapeutic potential of vascular endothelial growth factor 165 (VEGF₁₆₅). Lentiviral-mediated expression of Exp-Htt caused cell death and aggregate formation in human neuroblastoma SH-SY5Y and rat primary striatal cultures. Lentiviral-mediated VEGF₁₆₅ expression was found to be neuroprotective in both of these models. Unilateral stereotaxic vector delivery of Exp-Htt vector in adult rat striatum led to progressive inclusion formation and striatal neuron loss at 10 weeks post-transduction. Coinjection of a lower dose VEGF₁₆₅ significantly attenuated DARPP-32(+) neuronal loss, enhanced NeuN staining and reduced Exp-Htt aggregation. A tenfold higher dose VEGF₁₆₅ led to overt neuronal toxicity marked by tissue damage, neovascularization, extensive astrogliosis, vascular leakage, chronic inflammation and distal neuronal loss. No overt behavioral phenotype was observed in these animals. Expression of VEGF₁₆₅ at this higher dose in the brain of wild-type rats led to early mortality with global neuronal loss. This report raises important safety concerns about unregulated VEGF₁₆₅ CNS applications.
authors.affiliation: Division of Brain Sciences, Department of Gene Therapy, Faculty of Medicine, Centre for Neuroinflammation & Neurodegeneration, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Ellison
authors.forename: Antonio
authors.initials: A
authors.lastname: Trabalza
authors.forename: Veronica
authors.initials: V
authors.lastname: Tisato
authors.forename: Evangelos
authors.initials: E
authors.lastname: Pazarentzos
authors.forename: Shirley
authors.initials: S
authors.lastname: Lee
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Papadaki
authors.forename: Despoina
authors.initials: D
authors.lastname: Goniotaki
authors.forename: Sarah
authors.initials: S
authors.lastname: Morgan
authors.forename: Nazanin
authors.initials: N
authors.lastname: Mirzaei
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Mazarakis
mesh_terms: D000818:Animals; D016923:Cell Death; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D005822:Genetic Vectors; D057809:HEK293 Cells; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology*; D016086:Lentivirus / Q000235:genetics; D008297:Male; D009410:Nerve Degeneration / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents; D051381:Rats; D017207:Rats, Sprague-Dawley; D014161:Transduction, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism*
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A